Cocaine is a psychomotor stimulant affecting mammalian physiology and behavior following both acute and chronic patterns of administration. These adaptive changes result in the establishment of physical states representing tolerance, dependence, sensitization and withdrawal. Pharmacologically, the drug acts by inhibiting the synaptosomal uptake of catecholamines (including dopamine and norepinephrine), and serotonin (Gawin, "Cocaine Addiction: Psychology and Neurophysiology," Science, 251:1580-1586 (1991); Koob, "Drugs of Abuse: Anatomy, Pharmacology and Function of Reward Pathways," Trends in Neuroscience, 13:177-184 (1992)). Modulation of dopaminergic neurotransmission within the striatum, for example, is believed to underlie the rewarding and reinforcing properties associated with cocaine administration (Kuhar et al, "The Dopamine Hypothesis of the Reinforcing Properties of Cocaine" Trends in Neuroscience, 14:299-302 (1991)).
It is currently hypothesized that cellular plasticity within specific neural circuits underlies the behavioral and physiological alterations associated with psychomotor stimulant administration (for review, see Nestler, "Molecular mechanisms of drug addiction," J Neuroscience 12:2439-2450 (1992)). One such type of plasticity occurs at the nuclear level, and involves the regulated expression of specific sets of genes. For example, cocaine selectively regulates the pattern of expression of immediate early genes (IEGs), particularly those belonging to the Fos and Jun (i.e., AP-1) family of transcriptional regulatory factors, within the brain. Furthermore, such transcriptional regulation appears to be localized to those brain regions regulated by catecholaminergic input. For example, it is now firmly established that acute administration of cocaine induces expression of c-fos and jun B mRNA in the rat striatum (Graybiel et al., "Amphetamine and Cocaine Induce Drug-Specific Activation of the c-fos Gene in Striosome-Matrix Compartments and Limbic Subdivisions of the Striatum," Proc. Natl. Acad. Sci. USA, 87:6912-6916 (1990); Dragunow et al., "3,4 MethyleneDioxyMethamphetamine Induces Fos-like Proteins in Rat Basal Ganglia: Reversal With MK-801," Eur. J Pharmacol., 206:255-258 (1991); Hope et al., "Regulation of Immediate Early Gene Expression and AP-1 Binding in the Rat Nucleus Accumbens by Chronic Cocaine," Proc. Natl. Acad. Sci. USA, 89:5764-5768 (1992); Nguyen et al., "Differential Expression of c-Fos and Zif-268 in Rat Striatum After Haloperidol, Clozapine and Amphetamine," Proc. Natl. Acad. Sci. USA, 89:4270-4274 (1992); Young et al., "Cocaine Induces Striatal c-fos-Immunoreactive Proteins via Dopaminergic D1 Receptors," Proc. Natl. Acad Sci. USA, 88:1291-1295 (1991)), a brain structure regulated by catecholaminergic input and representing a crucial component of the neuronal circuitry underlying reward. The cerebellum also represents a brain structure in which c-fos mRNA levels are selectively elevated following acute cocaine administration (Iadarola et al., "Induction and Suppression of Proto-Oncogenes in Rat Striatum After Single and Multiple Treatments with Cocaine and GBR-12909," In NIDA research monograph series: Activation of immediate early genes by drugs of abuse (Grzanna et al., Eds.), 125:181-211 (1993); Clark et al., "Expression of c-fos mRNA in Acute and Kindled Cocaine Seizures in Rats," Brain Res., 582:101-106 (1992)). Studies have further shown that cerebellar c-fos mRNA levels rapidly increase following acute cocaine treatment (Iadarola et al., supra; Clark et al., supra), with chronic treatment resulting in a sensitization of the transcriptional response (Couceyro et al., "Cocaine Differentially Regulates Activator Protein-1 mRNA Levels and DNA Binding Complexes in the Rat Striatum and Cerebellum," Mol. Pharmacol., 46:667-676 (1994)). Thus, transcriptional plasticity appears to represent a cellular mechanism through which specific neural networks respond and adapt to psychomotor stimulant administration. By contrast, the hippocampus represents a transcriptionally quiescent brain structure following acute administration of psychomotor stimulants. Thus, such brain region specific transcriptional changes associated with psychomotor stimulant administration are likely to be related to reinforcement and addiction.
An important area of current research involves identification of additional psychomotor stimulant regulated genes. Identification of such genes will increase our understanding of the molecular events underlying both short- and long-term cellular changes resulting from administration of psychomotor stimulant drugs, and may potentially lead to the development of therapeutic agents which mediate effects of psychomotor drugs.